IL-1α, Innate Immunity, and Skin Carcinogenesis: The Effect of Constitutive Expression of IL-1α in Epidermis on Chemical Carcinogenesis

Abstract

Tumor promoters such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are proinflammatory agents, and their mechanism of action in epithelial carcinogenesis has been linked to the release of IL-1α and the induction of chronic inflammation in skin. To test the role of IL-1α and inflammation in models of cutaneous carcinogenesis, we used our previously described FVB/N transgenic mice overexpressing 17-kDa IL-1α in the epidermis under the keratin 14 (K14) promoter. Strikingly, the K14/IL-1α mice were completely resistant to papilloma and carcinoma formation induced by a two-stage DMBA/TPA protocol, while littermate controls developed both tumor types. K14/IL-1α mice crossed with the highly sensitive TG.AC mice, constitutively expressing mutant Ha-Ras, also failed to develop papillomas or carcinomas. When the K14/IL-1α transgene was bred onto a recombinase-activating gene-2-deficient background, the resistance persisted, indicating that innate, but not acquired, mechanisms may be involved in the resistance to the initiation/promotion model. As an alternative approach, a complete carcinogenesis protocol using repetitive application of DMBA alone was applied. Surprisingly, although the IL-1α mice still did not develop papillomas, they did develop carcinomas de novo at an accelerated rate compared with controls. We conclude that constitutive IL-1α expression rendered FVB mice completely resistant to carcinomas that required evolution from prior papillomas, but facilitated carcinomas that did not evolve from papillomas, as in the complete carcinogenesis protocol. Thus, the role of IL-1α and, by extension that of other proinflammatory factors, in epithelial carcinogenesis are more complex than previously appreciated. These mice may provide a mechanism to investigate the validity of these models of human skin tumorigenesis.

TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion. A role for TNF-α in keratinocyte migration?

“…TNF-a-induced MMP-9 protein expression was significantly decreased by neutralization of avb6 compared with control (b; asterisk denotes P ¼ 0.0022). Data are representative of at least two independent experiments response of the skin to injury (Murphy et al, 2003). Little is known regarding the precise role of TNF-a during wound healing and conflicting evidence exists in the literature (Buck et al, 1996;Hubner et al, 1996;Lee et al, 2000;Mori et al, 2002).…”

Mechanisms of SEPA 0009-Induced Tumorigenesis in v-rasHa Transgenic Tg.AC Mice

“…For example, resorcinol, which was negative in the rat and mouse NTP bioassay, induced papillomas in Tg.AC mice when given at a level that also caused inflammation in the skin (Sistare et al, 2002). However, investigations into the role of inflammation in tumorigenesis in Tg.AC mice have also produced contradictory results, necessitating further research (Albert et al, 1996;Murphy et al, 2003). Tumor development in SEPA 0009-treated Tg.AC mice, which is preceded by a severe and chronic skin irritation, is consistent with the response of Tg.AC mice to sustained irritation and inflammation.…”

Acquired and innate immunity to polyaromatic hydrocarbons

“…Moore et al (1999) reported that proinflammatory cytokines were important for de novo carcinogenesis and mice deficient in TNF-α are resistant to skin carcinogenesis. However, constitutive expression of IL-1α in the epidermis of FVB mice rendered them completely resistant to skin carcinogenesis (Murphy et al, 2003).…”

“…Moore et al (1999) reported that proinflammatory cytokines were important for de novo carcinogenesis and mice deficient in TNF-α are resistant to skin carcinogenesis. However, constitutive expression of IL-1α in the epidermis of FVB mice rendered them completely resistant to skin carcinogenesis (Murphy et al, 2003).Studies from our laboratory have demonstrated that topical application of DMBA, B(a)P and 3-methylcholanthrene (3-MC) -three carcinogenic polyaromatic hydrocarbons -results in the induction of a contact hypersensitivity response, which is a T-cell-mediated immune response to topically applied haptens (Figure 1) (Klemme et al, 1987;Anderson et al, 1995). The response fulfills all of the requirements of an acquired immune response including antigen specificity and the ability to be adoptively transferred with cell suspensions from draining lymph nodes (Klemme et al, 1987).…”